Refractory Chronic Cough Improvement Via NAL ER (RIVER)

Refractory Chronic Cough Clinical Trial

— RIVER  

Official title:

A Phase 2, Double-Blind, Randomized, Placebo-Controlled, Two-Period Crossover Efficacy and Safety Study of Nalbuphine ER Tablets for the Treatment of Refractory Chronic Cough

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05962151
• Other study ID #: NAL04-201
• Status: Recruiting
• Phase: Phase 2
• Start date: November 30, 2023
• Est. completion date: October 2024

Study information

• Verified date: April 2024
• Source: Trevi Therapeutics
• Contact: Sherry Minor
• Phone: 203-684-1308
• Email: Sherry.Minor[@]trevitherapeutics.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A 2-period crossover study for the treatment of cough in patients with Refractory Chronic Cough via Nalbuphine ER (NAL ER). Each period will last 21 days and are separated by 21 days. Subjects will be randomized in Treatment Period 1 to either NAL ER or matching placebo and evaluated for 21 days. After completion of the first phase, subjects who received NAL ER will crossover to placebo and subjects who received placebo will crossover to NAL ER to complete Treatment Period 2.

Description:

A double-blind, randomized, placebo-controlled, 2-period crossover study for the treatment of cough with NAL ER in subjects with Refractory Chronic Cough.

Based on the screening cough monitor results, the study will enroll subjects in a 1:1 ratio to subgroups of 10-19 coughs/hour and ≥20 coughs/hour.

After meeting eligibility during the screening period, subjects will be randomly assigned to one of the following sequences:

• NAL ER in Treatment Period 1, followed by Placebo (PBO) in Treatment Period 2 OR

• PBO in Treatment Period 1, followed by NAL ER in Treatment Period 2.

Each treatment period lasts 21 days and are separated by a 21-day washout period. Subjects on NAL ER will have the dose titrated from 27 mg once a day (QD) to 108 mg twice a day (BID).

Study visits in each treatment period will be at Day -1 for Baseline cough assessments, and at Days 6, 13, and 20. Subjects will have blood drawn for pharmacokinetic (PK) analysis of nalbuphine plasma concentration. Subjects will also complete questionnaires for efficacy evaluations and undergo safety evaluations including an electrocardiogram (ECG).

At the Screening and Baseline visits and on Days 6, 13, and 20 during each treatment period, site staff will place an electronic cough monitor on the subject, which will be worn for a 24-hour recording period to assess cough frequency. At the end of each recording session (Days 7, 14, and 21), the monitor will be removed at home by the subject, and the subjects will complete Patient Reported Outcomes (PROs) questionnaires in the electronic diary.

Subjects will be taken off study drug at the end of Treatment Period 2 and followed off treatment for an additional 2 weeks.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: October 2024
• Est. primary completion date: September 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Key Inclusion Criteria:

• Diagnosis of refractory chronic cough (RCC) for at least one year

• Chest radiograph or CT of thorax within 24 months or during screening not demonstrating any significant abnormalities contributing to RCC

Exclusion Criteria:

• Diagnosis of sleep apnea

• Respiratory tract infection within 6 weeks of Baseline

• History of bronchiectasis, COPD, or IPF

• History of uncontrolled asthma

• Current smokers/vapers, quit smoking with <=12 months, using nicotine supplements, or history of >=20 pack years

• History of major psychiatric disorder

• History of substance abuse

• Pregnant or lactating females

• Known intolerance to opioids

• Abnormal kidney or liver functions based on Screening lab results.

• Known hypersensitivity to nalbuphine or to NAL ER excipients

• Previous participation in a nalbuphine ER clinical study

• Use of opiates, benzodiazepines, or MAOIs within 14 days of Baseline

• Use of pregabalin, gabapentin, thalidomide for treatment of cough within 14 days of Baseline

• Use of ACE inhibitors within 12 weeks of Baseline

• Use of a medication having a "known risk" of Torsade de Pointes (categorized as "KR" on the Credible Meds® website.) 4 weeks prior to Baseline

• Use of unstable doses of medications associated with a potential risk of QT prolongation but not clearly associated with Torsade de Pointes within 4 weeks of screening.

• Use of unstable doses of cough suppressants within 14 days of Baseline

• Use of unstable doses of medications that affect serotonergic neurotransmission that may cause serotonin syndrome with opioids within14 days of Baseline

• Use of unstable doses of P450 isozyme inhibitors/inducers within 14 days of Baseline

Related Conditions & MeSH terms

• Chronic Cough
• Cough
• Refractory Chronic Cough

Intervention

Drug:
• Nalbuphine ER
Oral tablets
• Placebo
Oral tablets

Locations

Country	Name	City	State
Canada	McMaster University Medical Centre	Hamilton	Ontario
Canada	Inspiration Research	Toronto	Ontario
Canada	CIC Mauricie Inc.	Trois-Rivières	Quebec
United Kingdom	Belfast City Hospital	Belfast	Northern Ireland
United Kingdom	University Hospitals Birmingham NHS Foundation Trust	Birmingham	West Midlands
United Kingdom	Accellacare Northamptonshire	Corby	Northamptonshire
United Kingdom	Hull and East Yorkshire Hospitals NHS Trust - Castle Hill Hospital	Cottingham	East Riding Of Yorkshire
United Kingdom	Accellacare Warwickshire	Coventry	Warwickshire
United Kingdom	Kings College Hospital NHS Foundation Trust	London	Greater London
United Kingdom	University Hospital of South Manchester NHS Foundation Trust (UHSM) - Wythenshawe Hospital	Manchester	Greater Manchester
United Kingdom	North Tyneside General Hospital - Northumbria Healthcare NHS Foundation Trust	North Shields	Tynemouth
United Kingdom	Accellacare North London	Northwood	Middlesex
United Kingdom	Accellacare Yorkshire	Shipley	Yorkshire
United Kingdom	Accellacare South London	Sidcup	Kent

Sponsors (1)

Lead Sponsor	Collaborator
Trevi Therapeutics

Countries where clinical trial is conducted

Canada,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	24 hr cough frequency	Relative change in frequency (coughs per hour) versus Placebo	Day 21 versus Baseline
Secondary	Number of participants with treatment related adverse events, as assessed by CTCAE v.5.0	Adverse events, clinical labs, vital signs, physical exams, electrocardiograms	Baseline through follow-up
Secondary	Subjective Opiate Withdrawal Scale	16 item questionnaire for 14 days following last dose of study drug	Daily for 14 days after last dose in Period 2
Secondary	24 hour cough frequency	Relative change in frequency (coughs per hour) versus Placebo	Days 7 and 14 versus Baseline
Secondary	24 hour cough frequency	Proportion of responders with >=30%, 50% and 75% reduction in frequency versus Placebo	Days 7, 14, and 21 versus Baseline
Secondary	Awake cough frequency	Relative change in frequency (coughs per hour) versus Placebo	Days 7, 14, and 21 versus Baseline
Secondary	Sleep cough frequency	Relative change in frequency (coughs per hour) versus Placebo	Days 7, 14, and 21 versus Baseline
Secondary	Cough Severity Visual Analogue Scale	1 item scale with minimum score of 0 (no cough) to 10 (worst cough) versus Placebo	Days 7, 14, and 21 versus Baseline
Secondary	Leicester Cough Questionnaire	19 item questionnaire with a grading of 1 (all the time ) to 7 (none of the time) versus Placebo	Day 21 versus Baseline
Secondary	Patient-Reported Cough Frequency (change)	Change versus Placebo	Days 7, 14, and 21 versus Baseline
Secondary	Patient-Reported Cough Frequency (proportion)	Proportion of responders with improvement in at least one category versus Placebo	Days 7, 14, and 21 versus Baseline
Secondary	Patient Global Impression of Cough Severity	1 item question with a grading from "no cough, to mild, moderate or severe" versus Placebo	Days 7, 14, and 21 versus Baseline
Secondary	Patient Global Impression of Cough Change	1 item question with a 7 point grading from "much better to much worse" versus Placebo	Days 7, 14, and 21 versus Baseline
Secondary	Clinicians Global Impression of Cough Severity	1 item question with a grading from "no cough, to mild, moderate or severe" versus Placebo	Day 21 versus Baseline (both treatment periods)
Secondary	Clinicians Global Impression of Cough Change	1 item question with a 7 point grading from "very much improved to very much worse" versus Placebo	Day 21 versus Baseline (both treatment periods)